Histone tails contain highly conserved lysine residues that can be acetylated on their ε-amino groups. Each acetylation event eliminates another positive charge and potentially weakens the electrostatic interactions that tether the octamer tails to the DNA phosphate backbone. Histone acetylation may affect chromatin structure by at least two different mechanisms. First, the net reduction in positive charge could lead to destabilization and consequent dissociation of nucleosomes, thus allowing access of transcription factors and RNA polymerase to the DNA. Second, histone acetylation may inhibit the stacking of nucleosomes into the solenoid structure and thus the formation of higher-order structure. In addition, several cellular proteins are also regulated by acetylation of their lysine residues. The acetylation/deacetylation of proteins regulates the function of proteins in several ways.
Two families of deacetylase enzymes have been identified: the histone deacetylases, or HDACs, and the Sir2 (silent information regulator)-like family of NAD-dependent deacetylases, or sirtuins. The HDACs and sirtuin enzymes are therapeutic targets in a variety of human diseases including cancer, diabetes, inflammatory disorders and neurodegenerative disease. For example, modulation of sirtuin activity has been shown to impact the course of several aggregate-forming neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and spinal and bulbar muscular atrophy. Sirtuins can influence the progression of neurodegenerative disorders by modulating transcription factor activity and directly deacetylating proteotoxic species.
Sirtuin activation through the polyphenol resveratrol can regulate metabolism and the aging processes in yeast and higher organisms, and SIRT1 activation can alleviate metabolic diseases in mice (Lakshimanrasimhan, Aging, 5:151-154, 2013). Resveratrol (RSV) is a natural compound found in the skin of red grapes and other food products that seems to have a wide spectrum of biological activities which includes phytoalexin to protect plants against the fungal infection (Plant Mol Biol, 15:325-335, 1990), as a cardioprotective agent (Nutr Res, 28:729-737, 2008), partially preventing platelet aggregation (Clin Chim Acta, 246:163-182, 1996; J Nat Prod, 60:1082-1087, 1997), and inhibiting 5-lipoxygenase activity and prostaglandin synthesis (Mol Pharmacol 54:445-451, 1998; Biochem Pharmacol 59:865-870, 2000). Use of resveratrol in the pharmaceutical and cosmetic fields is described in, for example, WO9959561, WO9958119, EP0773020, FR2766176, and WO9904747.
There is an interest in resveratrol as a chemo-preventive agent in cancer therapy based on its striking inhibitory effects on cellular events associated with cancer initiation, promotion and propagation (Science, 275:218, 1997; J Nutr Biochem, 16:449, 2005; Cancer Lett, 269:243, 2008). Previous studies on in vitro anti-cancer effects of resveratrol showed that it interacts with multiple molecular targets and has positive effects on different cancer cells including breast, skin, gastric, colon, prostate, leukemia (Nat Rev Drug Discov, 5:493, 2006). However, the study of pharmacokinetics of resveratrol in humans concluded that even high doses of resveratrol might be insufficient to achieve resveratrol concentrations required for the systemic prevention of cancer (Toxicol Appl Pharmacol, 224:274, 2007) because of its lower bioavailability and its quick metabolization as sulfo and glucuro conjugates (Cancer Epidemiol. Biomarkers Prev, 16:1246, 2007, J Nutr, 136:2542, 2006 Drug Metab Dispos, 32:1377, 2004 Mol Nutr Food Res, 49:482, 2005). Other studies have focused on the design and synthesis of novel resveratrol analogs with more potent antitumor activity and a better pharmacokinetic profile (J Med Chem, 46:3546, 2003 J Med Chem, 48:1292, 2005, J Med Chem, 48:6783, 2005 Cancer Chemother Pharmacol, 63:27, 2008, J Med Chem 49, 7182, 2006 J. Agric. Food Chem. 58, 226, 2010).
There are reports on a boronic acid biostere of combrestatin A-4 and a chalcone analog of combrestatin A-4 as potent anti-cancer agents (Chem Biol, 12:1007, 2005, Bioorg. Med Chem, 18, 971, 2010). In addition, boronic acid and ester compounds have been reported to display a variety of pharmaceutically useful biological activities as proteosome inhibitors and several important functions including reduction in the rate of muscle protein degradation, reduction in the activity of NF-kB in a cell, inhibition in the cyclin degradation in a cell, inhibition in the growth of cancer cells, and inhibition of antigen presentation in a cell (Cell, 79:13-21, 1991; Cancer Res, 70:1970-80, 2010, Bioorg Med Chem Lett, 10:3416-9, 2010 J. Med Chem, 51:1068-1072, 2008, U.S. Pat. Nos. 4,499,082, 5,187,157, 5,242,904, 5,250,720, 5,169,841, 5,780,454, 6,066,730, 6,083,903, 6,297,217).
It is an object of this invention to provide compounds, compositions and methods to activate deacetylase enzymes. It is also an object of the present invention to provide compounds, compositions and methods for the treatment of cancer, cardiovascular disease, inflammation, obesity, diabetes, or a neurodegenerative disease related to the activation of deacetylase enzymes.